ReviewPeripheral NK cell phenotypes: multiple changing of faces of an adapting, developing cell
Introduction
Peripheral NK cells have been identified both in humans and rodents as a discrete lymphocyte subset expressing the low affinity receptor for the Fc portion of IgG (FcγRIIIA, CD16), CD56 and CD161 (NKR-P1A, human), or CD161 (NKR-P1C, NK1.1, rodents) in the absence of T cell receptor (TCR) and its associated CD3 complex (reviewed in Trinchieri (1989)). Phenotypically distinct populations among them have been proposed to represent independent subsets, specialized to primarily mediate one or more NK cell functions based on different levels of spontaneous cytotoxicity or of cytokines produced. Phenotypically distinguishable stages of NK cell development from their hematopoietic progenitors have been defined, and a minor population of human peripheral NK cells shares the phenotype (NKR-P1A/CD161+CD56−) of the relatively immature NK cells derived from cultures of CD34+ or Lineage (Lin)− hematopoietic progenitors (Bennett et al., 1996, Lanier et al., 1994). The results of our analyses of progenitor–progeny relation at the single cell level, and of the direct modulating effects of cytokines and cellular ligands on NK cell phenotype, functions, and development support the conclusion that peripheral NK cell phenotypes deviating from that of the majority of mature NK cells correspond to developmental stages or states of cell activation, rather than independent and unrelated bona fide ‘subsets’. Here, we discuss our data on this topic in the context of the current literature on NK cell development.
Section snippets
Surface phenotypes of peripheral NK cells
All peripheral human NK cells, like their rodent counterparts, express CD161 (Loza et al., 2002a). Most of them co-express CD56 (absent in the mouse) at relatively low density (CD56+lo), and most CD161+CD56+lo NK cells are CD16 (FcγRIIIA)+ (Perussia, 1998). NK cells also bear the low affinity receptor for IL-2 (IL-2Rβ and common γ-chain, CD122); a minor population of them, expressing highest CD56 levels (CD56+hi), also expresses the high affinity IL-2Rα (CD25) (Loza and Perussia, 2004b, Nagler
Developmental relationship between peripheral NK cell populations
Based on apparent differential distribution of several of the differentiation antigens discussed above, it has been suggested that distinct NK cell subsets may exist, with unclear relation to the majority of NK cells and specialized to perform one or more NK cell functions. Such have been proposed to be, e.g., a subset bearing receptors for the multi-lineage hematopoietic growth factor stem cell factor (SCF) (Matos et al., 1993), and the CD56bright subset, mostly CD16− and partially KIR−, with
Cytokine-mediated regulation of accumulation of peripheral mature and immature NK cells
The data discussed support the contention that peripheral NK cells develop through at least two sequential stages functionally characterized by exclusive production of type 2 or type 1 cytokines, and the hypothesis that this progression is regulated, on a cellular basis, by any factor or cellular ligand that affects proliferation/survival of the immature (CD161+ type 2 cytokine+hi) cells or their ability to acquire a phenotype responsive to IL-12 (i.e. a functional IL-12R, β2 chain).
Direct modulating effects of cytokines and receptor ligands induce ‘activated’ phenotypes
Cytokines and ligands on the target cells that engage receptors on NK cells can directly induce functional effects (e.g., FcγRIIIA- and activating receptors-mediated degranulation and consequent cytotoxicity), and regulate transcription, or expression, of genes encoding cytokines and molecules relevant to NK cell immunobiology. Thus, adding to and independent from differentiation-related phenotypic changes is the cytokine- and ligand-induced modulation (possibly transient) of established
NK cell development from immature progenitors: steps similar to those in peripheral cells
The developmental process of NK cells from their hematopoietic progenitors has been analyzed in vitro and in vivo primarily to define its cytokine-mediated regulation, and the analysis of knockout murine models has been essential for this (reviewed in Williams et al. (1998)). Very few studies have addressed the question of the functional development of these cells.
Human NK cell development has been analyzed in cultures of CD34+, Lin− cells, or CD7+Lin− cells with IL-2, IL-15, or Flt3L and IL-15
Implications to NK cell immunobiology
One major conclusion from the above-discussed evidence is that the rules and facts of hematopoiesis apply to NK cells. The hematopoietic compartment is leaky: small proportions of immature progenitor cells (including CD34+ cells containing stem cells) and immature cells of several myeloid lineages have been known for long time to be present in the periphery, where they are capable of proliferation and differentiation, like CD161+CD56− NK cells are. Most, if not all, B cells differentiate in the
Hypotheses for future developments
Cytokines (IL-15, IL-12, IL-18, IFN-α) produced by accessory cells play an essential role in NK cell development and activation in non-pathological conditions. This leads to the proposal that the interaction between NK and accessory cells of innate immunity is central to the accumulation and functional modulation of NK cells at possibly distinct developmental stages, and that these may differ depending on the type of accessory cells (and thus cytokines) involved in pathogen recognition.
Conclusions
The definition of the developmental relationships between phenotypically and functionally distinct peripheral NK cell populations, and the appreciation that, like nucleated hematopoietic cells, most peripheral NK cells are neither ‘static’ nor fully functionally differentiated, and adapt to the cytokine environment with differentiation-dependent or -independent functional and phenotypic modulation, provide a much simplified framework in which to test hypotheses on the molecular and cellular
Acknowledgments
The work from our laboratory discussed here was supported, in part, by USPHS grants AI055842 and CA56036. We thank L. Azzoni, I. Bennett, E. Santos, L. Zamai, and O. Zatsepina, past members of the laboratory, for having contributed to these studies with the production of reagents, establishments of experimental systems and techniques, and discussions; B. Abebe for technical assistance; J. Faust and J. McCormick (KCC Flow Cytometry Facility) for expert help in analysis and sorting; V. Berghella
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